Preparation of pyrazole and its derivatives

ABSTRACT

A process for preparing pyrazole and its derivatives of the formula I ##STR1## where R 1 , R 2 , R 3  and R 4  are each hydrogen, halogen, nitro, carboxyl, sulfonyl or C-organic radicals, from alpha,beta-unsaturated carbonyl compounds of the formula II ##STR2## and hydrazine or hydrazine derivatives of the formula III 
     
         H.sub.2 N--NHR.sup.4                                       III 
    
     wherein, initially without additional diluent, an alpha,beta-unsaturated carbonyl compound of the formula II is reacted with hydrazine or a hydrazine derivative of the formula III, and the resulting reaction mixture is reacted in another step with a mixture of sulfuric acid and iodine or a compound which liberates iodine or hydrogen iodide.

The present invention relates to a process for preparing pyrazole andits derivatives of the formula I ##STR3## where R¹, R², R³ and R⁴ areeach hydrogen, halogen, nitro, carboxyl, sulfonyl or C-organic radicals,from alpha,beta-unsaturated carbonyl compounds of the formula II##STR4## and hydrazine or hydrazine derivatives of the formula III

    H.sub.2 N--NHR.sup.4                                       III

EP-A 402 722 discloses the preparation of pyrazole and its derivativesfrom alpha,beta-unsaturated carbonyl compounds and hydrazine orhydrazine derivatives. In the process described therein, eitherpyrazoline or a carbonyl compound and a hydrazine derivative is reactedin a mixture of sulfuric acid and iodine or a compound which liberatesiodine or hydrogen iodide in situ to give the required pyrazole. Theyields in the described examples average 78% based on the hydrazinederivative employed.

It is an object of the present invention to prepare pyrazole and itsderivatives in a simple manner with improved yields and in higherpurity.

We have found that this object is achieved by a process for preparingpyrazole and its derivatives of the formula I ##STR5## where R¹, R², R³and R⁴ are each hydrogen, halogen, nitro, carboxyl, sulfonyl orC-organic radicals, from alpha,beta-unsaturated carbonyl compounds ofthe formula II ##STR6## and hydrazine or hydrazine derivatives of theformula III

    H.sub.2 N--NHR.sup.4                                       III

wherein, initially without additional diluent, an alpha,beta-unsaturatedcarbonyl compound of the formula II is reacted with hydrazine or ahydrazine derivative of the formula III, and the resulting reactionmixture is reacted in another step with a mixture of sulfuric acid andiodine or a compound which liberates iodine or hydrogen iodide.

In this process, initially an alpha,beta-unsaturated carbonyl compoundII is mixed with hydrazine or a hydrazine derivative III whilemaintaining the temperature in the reaction medium during the admixturefrom to 100° C., preferably 10° C. to 70° C., in particular 20° C. to50° C. Since the reaction of alpha,beta-unsaturated carbonyl compoundsII with hydrazine or a hydrazine derivative III is exothermic, it may benecessary to cool the reaction mixture during the admixture. For themixing it is immaterial which of the reactants is introduced first orwhether the starting materials are introduced into the reaction volumesimultaneously but separately. Mixing is completed normally by stirringat the mixing temperature for from 10 minutes to 60 minutes after theaddition is complete.

Findings to date indicate that longer stirring times have a negligibleeffect on the completion of the reaction.

The starting materials are generally reacted together in approximatelythe stoichiometric amounts, the ratio of carbonyl compound II tohydrazine derivative III normally being from 1:0.65 to 1:1.25 mol/mol. Adifferent ratio of the reactants has a negligible effect on the progressof the reaction and is not worthwhile for economic reasons.

Hydrazine or the hydrazine derivative III can be used either in the formof the hydrates or of the free bases or also in the form ofcorresponding hydrazonium salts for the present process. Use of saltswhich are insoluble in the reaction medium may lead to losses of yieldowing to inadequate mixing. The hydrates or the free bases of thehydrazine derivatives III are preferably used.

The process is based on the principle of initially forming, by reactionof hydrazines with α,β-unsaturated carbonyl compounds, the correspondingpyrazolines and secondary products. Workup by distillation after removalof the water of reaction provides only moderate yields because thepyrazolines are accompanied by the byproducts which are formed byaddition of the pyrazolines onto the initial carbonyl compounds andwhich in turn may form hydrazones and azines with the hyrazines.

The resulting reaction mixture is subsequently, without further workup,reacted with a mixture of sulfuric acid and iodine or a compound whichliberates iodine or hydrogen iodide. The procedure for this is normallyas stated in EP-A 402 722, ie. a mixture of sulfuric acid and iodine ora compound which liberates iodine or hydrogen iodide is heated to from50° C. to 250° C., preferably 70° C. to 200° C., in particular 100° C.to 180° C. and the reaction mixture from the first stage is added atthis temperature.

It is also possible to introduce the reaction mixture from the firststage into the mixture of sulfuric acid and iodine or a compound whichliberates iodine or hydrogen iodide at lower temperatures, for example10°-30° C. However, for technical reasons, it is advantageous to carryout the addition at a higher temperature because salts are formed onmixing, and stirring of the reaction mixture becomes more difficult.Findings to date indicate that the temperature during the addition hasno effect on the yield of the reaction.

This second stage probably essentially obeys the same principle as thereaction described in EP-A 402 722. According to this, sulfuric acid isgenerally used in a concentration of not less than 30% by weight. Thesulfuric acid is normally from 40 to 99% by weight, preferably 45 to 95%by weight.

The amount of iodine or compound which liberates iodine or hydrogeniodide in this reaction is generally from 0.01 to 10 mol %, preferablyfrom 0.05 to 5 mol %, in particular from 0.1 to 2 mol %, based on thehydrazine or the hydrazine derivative III.

Besides iodine and hydrogen iodide, suitable compounds which liberateiodine or hydrogen iodide are, for example, alkali metal and alkalineearth metal iodides such as lithium iodide, sodium iodide, potassiumiodide, cesium iodide, magnesium iodide and calcium iodide as well asother metal iodides; it is possible in principle to employ all compoundsof iodine or hydrogen iodide which are able to liberate iodine orhydrogen iodide under the reaction conditions. These include, forexample, other organic iodine compounds such as alkali metal, alkalineearth metal or other metal hypoiodites, iodites, iodates and periodatesor organic iodine compounds, for example alkyl iodides such as methyliodide.

It has emerged that the optimal temperature for the dehydrogenationreaction or the oxidation of the iodide to iodine depends on thesulfuric acid concentration. The necessary temperatures for the reactionincrease as the sulfuric acid concentration decreases. It is thereforeadvisable to remove the water of reaction and the water introduced bythe use of hydrates by distillation during the reaction in order to keepthe temperature low.

The water removed from the reaction contains a large part of the addediodide as iodine and hydrogen iodide, which can be recovered afterreduction or neutralization with, for example, sodium bisulfite.

After the reaction is complete, the reaction mixture is allowed to cool,whereupon the pyrazole derivative generally crystallizes as sulfate.

To liberate the pyrazole, the reaction mixture is neutralized and theneutral mixture is extracted with an inert organic water-immisciblesolvent. The organic phase is subsequently dried and worked up in aconventional way. This results in crude pyrazoles which have a purity of85-90% which can be increased to 99% by a single distillation.

The abovementioned process is suitable for preparing pyrazole and itsderivatives of the general formula I ##STR7## where R¹, R², R³ and R⁴are each, independently of one another, hydrogen, halogen, nitro,carboxyl, sulfonyl or C-organic radicals.

Halogen means in this connection in particular fluorine, chlorine andbromine.

Suitable C-organic radicals are:

alkyl groups which can be straight-chain or branched, for example C₁-C₁₀ -alkyl, preferably C₁ -C₈ -alkyl, especially C₁ -C₆ -alkyl, itbeing possible for these radicals in turn to be interrupted by heteroatoms such as nitrogen, oxygen and sulfur and to carry substituents fromthe following group: nitro, carboxyl, sulfonyl, halogen, cycloalkyl,bicycloalkyl, aryl and hetaryl;

cycloalkyl groups or bicycloalkyl groups, for example C₃ -C₈ -cycloalkylor C₆ -C₁₀ -bicycloalkyl, it being possible for these radicals in turnto be interrupted by hetero atoms such as nitrogen, oxygen and sulfurand to carry substituents from the following group: nitro, carboxyl,sulfonyl, halogen, alkyl, cycloalkyl, bicycloalkyl, aryl and hetaryl;

aryl groups or hetaryl groups such as phenyl, naphthyl and pyridyl, itbeing possible for these radicals in turn to carry substituents from thefollowing group: nitro, carboxyl, sulfonyl, halogen, alkyl, cycloalkyl,bicycloalkyl, aryl and hetaryl.

The present process is particularly suitable for preparing pyrazolederivatives in which at least one of the radicals R¹ to R⁴ is nothydrogen.

Pyrazole and its derivatives are used, for example, as intermediates forpreparing pharmacologically active compounds, crop protection agents orelse dyes.

EXAMPLES

1. Preparation of 3-methylpyrazole

1.a Reaction of crotonaldehyde and hydrazine hydrate

169.1 g (2.415 mol) of crotonaldehyde were added to 115 g (2.3 mol) ofhydrazine hydrate keeping the temperature at 30° C. by cooling. Afterthe addition was complete, the mixture was stirred at 25° C. to 30° C.for a further 30 min.

1.b Conversion into 3-methylpyrazole

A mixture of 720.8 g (5.06 mol) of 68.8% strength sulfuric acid and 0.76g (5.1 mmol) of sodium iodide was heated to 155° C. and, at thistemperature, the mixture obtained in 1.a was added. Water was distilledout during the addition and for a further 30 min after the addition wascomplete. The water removed in this way was added to the reactionmixture, after it had been cooled to 70° C., to dilute it.

The diluted reaction mixture was adjusted to pH 8.5-9 with 15% strengthsodium hydroxide solution. A large part of the product resulted as anoil from this neutralization and can be removed by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 172.5 g of3-methylpyrazole (90.55% based on hydrazine hydrate) of 99% purity (HPLCdetermination). Boiling point 88° C./10 mbar.

2. Preparation of 4-methylpyrazole

2.a Reaction of methacrolein and hydrazine hydrate

177.1 g (2.53 mol) of methacrolein were added to 115 g (2.3 mol) ofhydrazine hydrate keeping the temperature at 30° C. by cooling. Afterthe addition was complete, the mixture was stirred at 25° C. to 30° C.for a further 30 min.

2.b Conversion into 4-methylpyrazole

A mixture of 720.8 g (5.06 mol) of 68.8% strength sulfuric acid and 1.00g (6.7 mmol) of sodium iodide was heated to 155° C. and, at thistemperature, the mixture obtained in 2.a was added. Water was distilledout during the addition and for a further 30 min after the addition wascomplete. The water removed in this way was added to the reactionmixture, after it had been cooled to 50° C., to dilute it.

The diluted reaction mixture was adjusted to pH 8.5 with 15% strengthsodium hydroxide solution. A large part of the product resulted as anoil from this neutralization and can be removed by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 170.5 g of4-methylpyrazole (89.52% based on hydrazine hydrate) of 99.2% purity(HPLC determination). Boiling point 82° C./7 mbar.

3. Preparation of 3,4-dimethylpyrazole

3.a Reaction of trans-2,3-dimethylacrolein with hydrazine hydrate

22.1 g (0.2625 mol) of trans-2,3-dimethylacrolein were added to 15.6 g(0.25 mol) of 80% hydrazine hydrate keeping the temperature at 30° C. bycooling. After the addition was complete, the mixture was stirred at 25°C. to 30° C. for a further 30 min.

3.b Conversion into 3,4-dimethylpyrazole

A mixture of 74.2 g (0.52 mol) of 68.8% strength sulfuric acid and 0.5 g(3.3 mmol) of sodium iodide was heated to 155° C. and, at thistemperature, the mixture obtained in 3.a was added. Water was distilledout during the addition and for a further 30 min after the addition wascomplete. The water removed in this way was added to the reactionmixture, after it had been cooled to 50° C., to dilute it.

The diluted reaction mixture was adjusted to pH 8.5 with 15% strengthsodium hydroxide solution. A large part of the product resulted as anoil from this neutralization and can be removed by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 21.4 g of3,4-dimethylpyrazole (88.4% based on hydrazine hydrate) of 99.2% purity.Boiling point 96° C./10 mbar.

4. Preparation of 1,5-dimethylpyrazole

4.a Reaction of crotonaldehyde with methylhydrazine

147 g (2.1 mol) of crotonaldehyde were added to 92 g (2 mol) ofmethylhydrazine keeping the temperature at 30° C. by cooling. After theaddition was complete, the mixture was stirred at 25° C. to 30° C. for afurther 30 min.

4.b Conversion into 1,5-dimethylpyrazole

A mixture of 626.7 g (4.4 mol) of 68.8% strength sulfuric acid and 0.66g (4.4 mmol) of sodium iodide was heated to 155° C. and, at thistemperature, the mixture obtained in 4.a was added. Water was distilledout during the addition and for a further 30 min after the addition wascomplete. The water removed in this way was added to the reactionmixture, after it had been cooled to 70° C., to dilute it.

The diluted reaction mixture was adjusted to pH 8.5-9 with 15% strengthsodium hydroxide solution. A large part of the product resulted as anoil from this neutralization and can be removed by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 167.8 g of1,5-dimethylpyrazole (86.7% based on methylhydrazine hydrate) of 99.2%purity. Boiling point 157° C./1013 mbar.

5. Preparation of 3-methylpyrazole

5.a Reaction of crotonaldehyde with hydrazine hydrate

147 g (2.1 mol) of crotonaldehyde were added to 125 g (2.0 mol) of 80%hydrazine hydrate keeping the temperature at 30° C. by cooling. Afterthe addition was complete, the mixture was stirred at 25° C. to 30° C.for a further 30 min.

5.b Conversion into 3-methylpyrazole

The mixture obtained in 5.a was added at 25° C. to a mixture of 449.2 g(4.4 mol) of 95% strength sulfuric acid and 0.66 g (4.4 mmol) of sodiumiodide keeping the temperature at 25° C. by cooling. The reactionmixture was then heated to 125° C. over the course of 45 min and kept at125° C. for 60 min. Water was distilled out during the heating up andduring the subsequent stirring. The water removed in this way was addedto the reaction mixture, after it had been cooled to 70° C., to diluteit.

The diluted reaction mixture was adjusted to pH 8.5-9 with 10% strengthsodium hydroxide solution. A large part of the product resulted as anoil from this neutralization and can be removed by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 143.4 g of3-methylpyrazole (87% based on hydrazine hydrate) of 99.5% purity.Boiling point 88° C./10 mbar. Comparison of the process according to theinvention with the process disclosed in EP-A-402 722

A. Preparation of 3-methylpyrazole by the process according to theinvention

A.1 Reaction of crotonaldehyde and hydrazine hydrate

73.5 g (1.05 mol) of crotonaldehyde were added to 62.5 g (1.0 mol) of80% hydrazine hydrate keeping the temperature at 30° C. by cooling.After the addition was complete, the mixture was stirred at 25° C. to30° C. for a further 30 min.

A.2 Conversion into 3-methylpyrazole

A mixture of 313.6 g (2.2 mol) of 68.8% strength sulfuric acid and 0.33g (2.2 mmol) of sodium iodide was heated to 155° C. and, at thistemperature, the mixture obtained in A.1 was added. Water was distilledout during the addition and for a further 30 min after the addition wascomplete. The water removed in this way was added to the reactionmixture after cooling.

The diluted reaction mixture was adjusted to pH 8.5 with 15% strengthsodium hydroxide solution. A large part of the product resulted as anoil from this neutralization and can be removed by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 73.4 g of3-methylpyrazole (89% based on hydrazine hydrate) of 99.5% purity (HPLCdetermination). Boiling point 88° C./10 mbar.

B Preparation of 3-methylpyrazole by the process disclosed in EP-A 402722

B.1 A mixture of 313.6 g (2.2 mol) of 68.8% strength sulfuric acid and0.33 g (2.2 mmol) of sodium iodide was heated to 155° C. and, at thistemperature, 62.5 g (1 mol) of 80% hydrazine hydrate and 73.6 g (1.05mol) of crotonaldehyde were added simultaneously. Water was distilledout during the addition and for a further 30 min after the addition wascomplete. The water removed in this way was added to the reactionmixture, after it had been cooled to 50° C., to dilute it.

B.2 The diluted reaction mixture was adjusted to pH 8.5 with 15%strength sodium hydroxide solution. A large part of the product resultedas an oil from this neutralization and was removable by decantation.Extraction of the aqueous phase with isobutanol and subsequent workup ofthe collected organic phases by distillation resulted in 62.4 g of3-methylpyrazole (75.7% based on hyrazine hydrate) of 99.5% purity.Boiling point: 88° C./10 mbar).

We claim:
 1. A process for preparing pyrazole and its derivatives of theformula I ##STR8## where R¹, R², R³ and R⁴ are each hydrogen, halogen,nitro, carboxyl, sulfonyl or C-organic radicals, fromalpha,beta-unsaturated carbonyl compounds of the formula II ##STR9## andhydrazine or hydrazine derivatives of the formula III

    H.sub.2 N--NHR.sup.4                                       III

wherein, initially without additional diluent, an alpha,beta-unsaturatedcarbonyl compound of the formula II is reacted with hydrazine or ahydrazine derivative of the formula III, and the resulting reactionmixture is reacted in another step with a mixture of sulfuric acid andiodine or a compound which liberates iodine or hydrogen iodide.
 2. Aprocess as claimed in claim 1, wherein the reaction of thealpha,beta-unsaturated carbonyl compound of the formula II withhydrazine or a hydrazine derivative of the formula III is carried out atfrom 0° C. to 100° C.
 3. A process as claimed in claim 1, wherein from40 to 99% by weight of sulfuric acid is used.
 4. A process as claimed inclaim 1, wherein from 0.01 to 10 mol % of iodine or of a compound whichliberates iodine or hydrogen iodide, based on the hydrazine or thehydrazine derivative of the formula III, are used.
 5. A process asclaimed in claim 1, wherein the reaction mixture obtained from thereaction of alpha,beta-unsaturated carbonyl compound of the formula IIwith hydrazine or a hydrazine derivative of the formula III is reactedat from 50° C. to 250° C. with a mixture of sulfuric acid and iodine ora compound which liberates iodine or hydrogen iodide.
 6. A process asclaimed in claim 1, wherein, during the reaction of the reaction mixtureobtained from the reaction of the alpha,beta-unsaturated carbonylcompound of the formula II with hydrazine or a hydrazine derivative ofthe formula III with a mixture of sulfuric acid and iodine or a compoundwhich liberates iodine or hydrogen iodide, the water of reaction presentin the mixture is removed.